Ixekizumab is FDA-indicated for the adult treatment of moderate to severe plaque psoriasis.[1] These adult patients are also candidates for systemic therapy or phototherapy. Research has not yet determined the safety and effectiveness in pediatric patients. Also, a brief discussion of psoriasis will follow, to understand better the mechanism of action of ixekizumab and its therapeutic use. 

Psoriasis is a common skin disease that affects about 2% of the US population. The most common form is plaque-type. Examples of types of psoriasis are inverse, guttate, and pustular. Plaque-type psoriasis is a chronic inflammatory skin disease with the following clinical characteristics: erythematous plaques with mica-like scales, sharply demarcated, that predominately affect the elbows, knees, gluteal cleft, and scalp. The skin plaques can be pruritic and slowly enlarge, and last for long periods. Approximately 30% of psoriasis patients have psoriatic arthritis in which there are five subtypes: arthritis mutilans, asymmetric, distal interphalangeal predominant, spondylitis, and symmetric. Arthritis mutilans, which accounts for less than 5% of psoriatic arthritis cases, is severe and can deform the small joints of the hands and feet. Asymmetric arthritis can affect any joint and may appear as sausage digits or dactylitis. Distal interphalangeal predominant can involve the fingers and toes, and it occurs in about 5% of psoriatic arthritis cases. Spondylitis or spondyloarthritis can affect the spine or pelvis, and it accounts for about 5% of psoriatic arthritis cases. Symmetric arthritis can present as a milder form of rheumatoid arthritis. The pathophysiology of psoriasis is not well understood.

There is a genetic aspect to the disease, with about 50% of the patients having a family history. Activated T cells appear to produce cytokines, which lead to hyperproliferation of keratinocytes and endothelial cells. Interleukin 17A (IL-17A) is an example of a cytokine that ixekizumab selectively inhibits. This hyperproliferation of keratinocytes and endothelial cells causes the erythematous plaques with mica-like scales to form on the elbows, knees, or scalp. Interleukin 17 is a crucial mediator in the mammalian immune system. It has six subtypes: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. Drugs that inhibit T cell activation, clonal expansion, or release (or activity) of proinflammatory cytokines can be effective in treating psoriasis.

Ixekizumab is a humanized monoclonal antibody (IgG) that selectively binds to interleukin 17A (IL-17A); this prevents interleukin 17A from binding to its receptor, the IL-17 receptor. Thus, this attenuates an inflammatory response mediated by interleukin 17A.[2] Psoriasis is caused by upregulated immune-related mechanisms that result in the activation of myeloid dendritic cells, which release interleukin 17A and other cytokines to activate T cells, including helper T cell T17. Along with other immune cells, T17 produces interleukin 17A. This proinflammatory cascade causes the proliferation of keratinocytes, angiogenesis, and movement of immune cells in psoriatic skin lesions. Thus, ixekizumab disrupts the pathogenic inflammatory cascade of psoriasis.

Ixekizumab was the object of study in three clinical phase trials: UNCOVER-1, UNCOVER-2, and UNCOVER-3.[3] UNCOVER-1 compared ixekizumab treatment in 1296 patients with psoriasis. Researchers randomly assigned patients to one of three groups. The two-week group received 160 mg starting dose at week zero, 80 mg every two weeks for 12 weeks. The four-week group received 160 mg starting dose at week zero, 80 mg every four weeks for 12 weeks. The placebo group received placebo for 12 weeks. The measurement of therapeutic efficacy was via the psoriasis area and severity index (PASI) score. A psoriasis area and severity index (PASI) score of 90 means that there was a 90% reduction in the psoriasis skin lesion area. At the end of 12 weeks, the two-week, four-week, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.9%, 64.6%, and 0.5%, respectively which were statistically significant when researchers compared the two treatment groups to placebo. UNCOVER-2 compared ixekizumab treatment in 1224 patients with psoriasis. The same UNCOVER-1 treatment regimens were used with the additional treatment group of etanercept 50 mg twice a week for 12 weeks. At the end of 12 weeks, the two-week, four-week, etanercept and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.7%, 59.7%, 18.7%, and 0.6%, respectively which were statistically significant when researchers compared the ixekizumab treatment groups to etanercept and placebo. UNCOVER-3 compared ixekizumab treatment in 1346 patients with psoriasis. The study used the same treatment regimens as in UNCOVER-2. At the end of 12 weeks, the two-week, four-week, etanercept, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 68.1%, 65.3%, 25.7%, and 3.1%, respectively which were statistically significant when researchers compared the ixekizumab treatment groups to etanercept and placebo. Etanercept binds to and inhibits the inflammatory cytokine, tumor necrosis factor (TNF). It is a synthetic TNF receptor. [4]

Ixekizumab administration is subcutaneous. Storage should be at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit). The ixekizumab dosage form should not be frozen, and it requires protection from light. The patient should discard the unused portion of the dosage. The patient should remove ixekizumab from the refrigerator and let it warm to room temperature, which will take approximately 30 minutes. Next, the patient should visually inspect the ixekizumab liquid, which should be free of particles and clear in color to a slightly yellow color. The patient should not shake the autoinjector or prefilled syringe. Lastly, the patient should inject ixekizumab subcutaneously at the directed dose. Recommended sites of injection are the thighs, upper arms, or abdomen, which the patient should rotate to prevent damage to the skin. The patient should avoid injecting sites that are affected by psoriasis, are bruised, or are damaged.

The recommended dosing is the following:

• 160 mg once on week 0
• 80 mg during weeks 2, 4, 6, 8, 10 and 12
• 80 mg every four weeks

There are no documented maximum doses for indicated use. There are no studies for dose adjustment in patients with renal or hepatic impairment. [5][6]

Commonly observed (over 10%) adverse drug reactions in patients who have treatment with ixekizumab are: neutropenia, hypersensitivity reactions, e.g., urticaria and angioedema, infections, injection site reactions, e.g., pain. Less commonly observed (less than 10%), adverse drug reactions are fungal skin infections (tinea), nausea, thrombocytopenia, and antibody development. Antibody development can decrease the concentrations of ixekizumab and decrease drug efficacy. Less than 1% observed adverse drug reactions are: Crohn disease, ulcerative colitis, oral candidiasis (Candida albicans infection), influenza, conjunctivitis, and rhinitis. Crohn disease and ulcerative colitis include exacerbations in susceptible patients.[7][8]

Patient contraindications include a severe hypersensitivity reaction, for example, anaphylaxis resulting from ixekizumab itself or any excipients in the dosage form. [9]